Drug Delivery For Various Molecules And Modalities

In this episode of Sit and Deliver, host Tom von Gunden talks with Merck VP of Pharmaceutical Sciences and Clinical Supply Allen Templeton about formulation and device considerations for combination products and other delivery systems deployed across a range of molecule types and sizes. The conversation takes them from small molecules, through peptides and mAbs, to large molecule biologics, across various routes of administration including oral, injectable, and inhalation.

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Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to another episode of Sit and Deliver, the series in which we hear from leading thinkers around considerations for drug delivery. My name is Tom von Gunden, Chief Editor at Drug Delivery Leader and your host for this series. For today's episode, I am joined by Allen Templeton, who is VP of Pharmaceutical Sciences and Clinical Supply at Merck.

Welcome, Allen.

Allen Templeton, VP of Pharmaceutical Services and Clinical Supply at Merck:

Hi, Tom. I'm happy to join you today.

Well, I appreciate you joining. It's my pleasure. So, let's just go ahead and dive in.

Allen, I know that, in addition to your role at Merck, you are also an officer at AAPS, the American Association of Pharmaceutical Scientists. And I know that, very recently, at the National Biotechnology Conference, you gave a presentation, and I'm just going to read that [title, which] is quite lengthy. That presentation was called “Navigating the Complexity of Biologics Product Design in the Era of Emerging Modalities and Drug Delivery.” So, I’m hoping you can elucidate and elaborate on some of those drug delivery related components of your presentation at that recent AAPS show.

So, first of all, I noticed that, in your presentation, you highlighted things like the increased diversity, complexity, and even the sheer size of the formulations being developed, from traditional small molecules through peptides and mAbs and on to significantly larger biologics, perhaps delivered via viral vectors and LNPs and things of that nature. So, can you comment on that increase in size and diversity and how that feeds into the thinking around approaches to drug delivery, whether that be oral administration or nasal or injectable or other methods?

Yes, I'm happy to, Tom. I think what we're seeing in the entire industry is a huge growth in different modalities. And this is driven by a desire to reach ever more difficult targets, in particular areas of biology. So. we're seeing a growth in areas like macrocyclic peptides and antibody drug conjugates and other antibody-conjugated variables like protein-drug conjugates and peptide-drug conjugates.

So, we're seeing a massive growth in modalities. And what that means for drug delivery overall is a move toward a higher number of injectable products than we've seen historically. So, when you move beyond small molecule, which drives you to oral tablets, you end up finding yourself with these other modalities in a situation where the only available or amenable drug delivery route is parenteral or injectable administration.

And so, with that comes devices as well. And drug-device combination products.

Gotcha. Yes, and I noticed that, also in your presentation, this is flipping it to the patient side. So, the folks that are going to be receiving these increasingly complex modalities, and increasingly often in injectable format: I noticed that in a subsection of one of your slides, you mentioned container closure. And under there, I noticed some very patient-centric concepts like design, ergonomics, human factors. So, when folks are thinking about device delivery, device design, how do those patient considerations come to mind or should they come to mind and factor in?

Thanks for the question, Tom. They absolutely have to come to mind. Not only is it required by regulators, but it's also integral for product design in this case. So, when you think about container closure and specifically in the context of drug-device combinations intended for parenteral delivery, one has to think about how the intended end user is going to use those products and what the instructions for use will be.

And it’s incumbent upon the company developing these products to also ensure the human factor studies that the product is not going to be used in error. That it is very clear which end of the product has the needle, when the product should be engaged such that the patient or caregiver doesn't inadvertently stick themselves.

So, these are the sort of things one has to consider right from the start of product design. And it impacts the container closure and the ultimate device selection through a number of different ways in terms of not only how the patient holds the product in their hand, the simplicity, the administration instructions, even what to do with the product once it has been administered. There's still danger from the patients sticking themselves or also just how long to leave the product in place before withdrawing it. All these sorts of considerations come to bear.

And one example would be, a lot of times with device products you’ll hear clicks; you'll have a click, an initiation that tells the patient or caregiver that the product is now engaged. And you'll have a click or a second click at the end when it reaches the end of administration. Those kinds of audible clues can be very powerful in helping the patient use the product correctly.

And these things in the past, companies got burned on this because they would put a product on the market that hadn't been adequately characterized in this regard, and there would be a lot of patient complaints and caregiver complaints. And now we've learned [that] we've got to design these products from the outset to have these sorts of considerations baked in.

And I imagine that, when the caregiver, so to speak, becomes increasingly the patient, him or herself, in a home use or self-administered scenario, it probably increases the need to make sure that those things are safe and effective.

Tom, you're absolutely right. It gets to the point when, in the patient's hands, you have to think about a further level of simplification relative to a caregiver who has medical training and practices day to day. The patient needs even another level of simplicity.

The other thing when you think about self-administration in the hands of patients is you've got to think about the elements not only of simplicity, but also then potential differentiation of your product versus another product. For example, ease of read of a pen injector dial can actually have prescribers preferentially prescribing one product over another. So, you have to think carefully about what your intended patient audience is, what the competitive marketplace looks like, and anything that you can provide from a competitive advantage standpoint, from an ease of use and patient administration standpoint. These things matter, especially for large volume products. Anything that companies can do to provide simplicity for administration is going to be helpful and could be differentiating.

Yes, great examples. Thanks for adding that detail.

I noticed another thing in your presentation [that] should be of interest for our drug delivery audience: You were talking again about combination products, and you offered a reminder about making sure that there's support for — and, I'll just quote you here — quote, “modality agnostic drug-device combination products,” end quote.

So, can you comment a little bit more about what you mean by and are thinking about when you use a term like modality agnostic?

Yes, so in an ideal world, we always have to think about the practicality of developing drug- device combination products for this very wide range of potential modalities that are available.

And it becomes — to have each one of those be bespoke becomes prohibitive from a cost standpoint for development, but also adds a lot of complexity in terms of how one thinks about supply chain and manufacturing. So, the ideal thing to be able to do in that case is to think about platforms that, let's say, drug-device combination platforms composed of the container closure system and the overall device component that one can then apply to a number of different, similar, let's say, modality and formulation types.

So that would be — then it's not always possible. But to have each of those be bespoke creates a huge burden.

Gotcha. Yeah, that makes a lot of sense.

So, Allen, for today, I just have one more question for you: In thinking about all of the pieces and parts and the people that have to be involved to bring these things to fruition during a product development cycle, I noticed that you also talked about the criticality of having what you call end-to-end collaboration among various stakeholders and SMEs.

So, can you illustrate that a little bit? What sorts of folks do you envision, in terms of who should be involved and at what point and how does that collaboration get up on its feet in an ideal process?

It’s a great question and one that we grapple with all the time. And I know others in the industry do as well.

When you think about drug-device combination products, by definition, you end up with a complex ecosystem. You end up with formulators, who are coming up with the composition and process for the actual formulation that goes in the product. You’re dealing with device engineers, who are thinking about the components and how those come together.

You're thinking about human factors, again going back to our earlier part of the conversation. You're thinking about people who [think about] how the product is going to be used. You also have quality and regulatory professionals. You may even have procurement individuals who are vendor-facing for some of these different supply chain components.

So, an R&D scientist has to be thinking, has to bring all that together. And then importantly, for the products to be of value and meaning to patients, they have to be translated into manufacturing and be able to be produced at scale. And some of these products are really large volume products. You take, like the GLP-1s that are on the market today in a device format. Those volumes of those products are massive. And so, manufacturability and translation into manufacturing is really important. All that has to come together.

So, what we try to do at Merck — and I think other companies do — is we try to bring that together through team structures. And have the right people at the table for the various milestones during the course of drug-device combination development and transition to manufacturing.

And the end-to-end piece comes in from thinking right out of discovery. One has to think about deviceability. One has to think about, from the outset, designing the molecules that can actually have the properties that will fit in the device and meet those device requirements.

And then all the way at the other end, one has to think all through development about developing the product in such a way that it's going to be feasible to be manufactured at scale and at volume. So that's the end-to-end piece and how it comes together. And it's even more important for these types of products, and especially as we're, again, moving into a more complex space than it's ever been before, I'd say it's more important.

I’ve developed a lot of small molecule products over the years, and it's another level of complexity associated with this. But it's absolutely critical because there are so many things that can be missed along the way. You can actually end up — they can apparently be small things that can actually hold up a product from being able to be successful in the market.

For example, you have a complex kit that has multiple components. If one part of that kit isn't available, well then you don't have a product. And it could be even some very simple component that might go into the product. So, that just gives you a sense about how all of these things have to really be integrated very carefully.

Yes. Well, Allen, I appreciate all of the insights, especially those words to the wise there at the end. And I want to thank you for joining me for this conversation for our Sit and Deliver series. I also want to thank our audience for joining us for this episode, and we'll see you next time